Bottom Line:
We have focused on the primary visual cortex, a region that is devoid of pathological changes and Lewy bodies; and two additional regions, the amygdala and anterior cingulate cortex which contain Lewy bodies at different disease stages but do not have as severe degeneration as the substantia nigra.False discovery rate analysis confirmed that 73 of these 79 lipid species were significantly changed in the visual cortex (q-value <0.05).Many of these changes in visual cortex lipids were correlated with relevant changes in the expression of genes involved in lipid metabolism and an oxidative stress response as determined by quantitative polymerase chain reaction techniques.

Affiliation: Neuroscience Research Australia, Sydney, New South Wales, Australia.

ABSTRACT

Background: We present a lipidomics analysis of human Parkinson's disease tissues. We have focused on the primary visual cortex, a region that is devoid of pathological changes and Lewy bodies; and two additional regions, the amygdala and anterior cingulate cortex which contain Lewy bodies at different disease stages but do not have as severe degeneration as the substantia nigra.

Methodology/principal findings: Using liquid chromatography mass spectrometry lipidomics techniques for an initial screen of 200 lipid species, significant changes in 79 sphingolipid, glycerophospholipid and cholesterol species were detected in the visual cortex of Parkinson's disease patients (n = 10) compared to controls (n = 10) as assessed by two-sided unpaired t-test (p-value <0.05). False discovery rate analysis confirmed that 73 of these 79 lipid species were significantly changed in the visual cortex (q-value <0.05). By contrast, changes in 17 and 12 lipid species were identified in the Parkinson's disease amygdala and anterior cingulate cortex, respectively, compared to controls; none of which remained significant after false discovery rate analysis. Using gas chromatography mass spectrometry techniques, 6 out of 7 oxysterols analysed from both non-enzymatic and enzymatic pathways were also selectively increased in the Parkinson's disease visual cortex. Many of these changes in visual cortex lipids were correlated with relevant changes in the expression of genes involved in lipid metabolism and an oxidative stress response as determined by quantitative polymerase chain reaction techniques.

Conclusions/significance: The data indicate that changes in lipid metabolism occur in the Parkinson's disease visual cortex in the absence of obvious pathology. This suggests that normalization of lipid metabolism and/or oxidative stress status in the visual cortex may represent a novel route for treatment of non-motor symptoms, such as visual hallucinations, that are experienced by a majority of Parkinson's disease patients.

Mentions:
In order to understand the underlying mechanisms that may contribute to regional changes in sphingolipid metabolism in PD, we assessed the expression of a selection of sphingolipid pathway genes in the full sample cohort by qRT-PCR. A simplified scheme depicting the sphingolipid pathway with relevant lipids and genes we have focused on is shown in Figure 4B. The gene expression data indicated a significant up-regulation of several genes involved in Cer and SM synthesis (SPTLC2, FVT1, DEGS1, SGMS1) in the PD VC (Fig. 5). This is in general agreement with the lipidomics LC/MS and ESI/MS data and suggests that transcriptional activation contributes to the increased levels of Cer and SM detected in the PD VC. The increased levels of SL detected in the PD VC were not associated with changes in UGT8a or Gal3ST1; two genes that regulate the conversion of Cer to galactosylceramide (GalCer) and SL, respectively (Fig. 5). This may indicate that increased levels of SL detected in the PD VC are the result of decreased SL catabolism or that the level of expression of UGT8a/Gal3ST1 is sufficient to catalyse the conversion of a proportion of the increased Cer (substrate) observed to GalCer and SL.

Mentions:
In order to understand the underlying mechanisms that may contribute to regional changes in sphingolipid metabolism in PD, we assessed the expression of a selection of sphingolipid pathway genes in the full sample cohort by qRT-PCR. A simplified scheme depicting the sphingolipid pathway with relevant lipids and genes we have focused on is shown in Figure 4B. The gene expression data indicated a significant up-regulation of several genes involved in Cer and SM synthesis (SPTLC2, FVT1, DEGS1, SGMS1) in the PD VC (Fig. 5). This is in general agreement with the lipidomics LC/MS and ESI/MS data and suggests that transcriptional activation contributes to the increased levels of Cer and SM detected in the PD VC. The increased levels of SL detected in the PD VC were not associated with changes in UGT8a or Gal3ST1; two genes that regulate the conversion of Cer to galactosylceramide (GalCer) and SL, respectively (Fig. 5). This may indicate that increased levels of SL detected in the PD VC are the result of decreased SL catabolism or that the level of expression of UGT8a/Gal3ST1 is sufficient to catalyse the conversion of a proportion of the increased Cer (substrate) observed to GalCer and SL.

Bottom Line:
We have focused on the primary visual cortex, a region that is devoid of pathological changes and Lewy bodies; and two additional regions, the amygdala and anterior cingulate cortex which contain Lewy bodies at different disease stages but do not have as severe degeneration as the substantia nigra.False discovery rate analysis confirmed that 73 of these 79 lipid species were significantly changed in the visual cortex (q-value <0.05).Many of these changes in visual cortex lipids were correlated with relevant changes in the expression of genes involved in lipid metabolism and an oxidative stress response as determined by quantitative polymerase chain reaction techniques.

Affiliation:
Neuroscience Research Australia, Sydney, New South Wales, Australia.

ABSTRACT

Background: We present a lipidomics analysis of human Parkinson's disease tissues. We have focused on the primary visual cortex, a region that is devoid of pathological changes and Lewy bodies; and two additional regions, the amygdala and anterior cingulate cortex which contain Lewy bodies at different disease stages but do not have as severe degeneration as the substantia nigra.

Methodology/principal findings: Using liquid chromatography mass spectrometry lipidomics techniques for an initial screen of 200 lipid species, significant changes in 79 sphingolipid, glycerophospholipid and cholesterol species were detected in the visual cortex of Parkinson's disease patients (n = 10) compared to controls (n = 10) as assessed by two-sided unpaired t-test (p-value <0.05). False discovery rate analysis confirmed that 73 of these 79 lipid species were significantly changed in the visual cortex (q-value <0.05). By contrast, changes in 17 and 12 lipid species were identified in the Parkinson's disease amygdala and anterior cingulate cortex, respectively, compared to controls; none of which remained significant after false discovery rate analysis. Using gas chromatography mass spectrometry techniques, 6 out of 7 oxysterols analysed from both non-enzymatic and enzymatic pathways were also selectively increased in the Parkinson's disease visual cortex. Many of these changes in visual cortex lipids were correlated with relevant changes in the expression of genes involved in lipid metabolism and an oxidative stress response as determined by quantitative polymerase chain reaction techniques.

Conclusions/significance: The data indicate that changes in lipid metabolism occur in the Parkinson's disease visual cortex in the absence of obvious pathology. This suggests that normalization of lipid metabolism and/or oxidative stress status in the visual cortex may represent a novel route for treatment of non-motor symptoms, such as visual hallucinations, that are experienced by a majority of Parkinson's disease patients.